X-Message-Number: 24830
Date: Sat, 16 Oct 2004 10:02:09 -0700 (PDT)
From: Doug Skrecky <>
Subject: walnuts and exercise versus endothelial aging

Med Hypotheses. 2004;63(4):719-23.
Optimizing endothelial nitric oxide activity may slow endothelial aging.
  The capacity of vascular endothelium to generate bioactive nitric oxide
(NO) decreases with advancing age, even in healthy subjects with a
relatively benign risk factor profile; this phenomenon may reflect
decreased expression of NO synthase, as well as increased production of
superoxide, and evidently contributes importantly to the increased
vascular risk associated with aging. Studies with cultured endothelial
cells suggest that the rate of endothelial aging is determined primarily
by the rate of cell turnover and the associated progressive shortening of
telomeres; endothelial cells transfected with the catalytic subunit of
telomerase--which preserves a youthful telomere length--do not show a
reduction in NO synthase expression after numerous doublings, in contrast
to the marked reduction observed in control cells. Also consistent with
this view is the fact that, following balloon denudation of arteries, the
regenerated endothelium makes less NO. In the vasculature of adults, the
rate of endothelial cell mitosis is evidently a reflection of the rate of
endothelial cell apoptosis. Numerous cell culture studies demonstrate
that physiological levels of NO protect endothelial cells from apoptosis
induced by a wide range of noxious stimuli--including vascular risk
factors such as oxidized LDL, angiotensin II, and hyperglycemia. In the
human vasculature, endothelial cells with disproportionately short
telomeres are found capping atheromatous lesions and in atheroma-prone
areas where blood flow is turbulent; these findings evidently reflect
increased endothelial cell turnover in regions where NO bioactivity is
relatively weak. It can be deduced that lifelong adherence to an
"endotheliophilic lifestyle" that optimizes vascular NO production, while
minimizing that of superoxide, will literally slow the rate of aging of
vascular endothelium, such that, at any given advanced age, the optimal
functional capacity of the vascular endothelium will be superior to that
of age-matched controls. These considerations underline the desirability
of actively promoting vascular health in younger and middle-aged
individuals in whom risk for vascular events may still be quite low. The
impact of lifelong caloric restriction on endothelial aging requires
further study, preferably in primates.

Circulation. 2004 Apr 6;109(13):1609-14. Epub 2004 Mar 22
A walnut diet improves endothelial function in hypercholesterolemic
subjects: a randomized crossover trial.
  BACKGROUND: Epidemiological studies suggest that nut intake decreases
coronary artery disease (CAD) risk. Nuts have a cholesterol-lowering
effect that partly explains this benefit. Endothelial dysfunction is
associated with CAD and its risk factors and is reversed by antioxidants
and marine n-3 fatty acids. Walnuts are a rich source of both antioxidants
and alpha-linolenic acid, a plant n-3 fatty acid. METHODS AND RESULTS: To
test the hypothesis that walnut intake will reverse endothelial
dysfunction, we randomized in a crossover design 21 hypercholesterolemic
men and women to a cholesterol-lowering Mediterranean diet and a diet of
similar energy and fat content in which walnuts replaced approximately
32% of the energy from monounsaturated fat. Participants followed each
diet for 4 weeks. After each intervention, we obtained fasting blood and
performed ultrasound measurements of brachial artery vasomotor function.
Eighteen subjects completing the protocol had suitable ultrasound
studies. Compared with the Mediterranean diet, the walnut diet improved
endothelium-dependent vasodilation and reduced levels of vascular cell
adhesion molecule-1 (P<0.05 for both). Endothelium-independent
vasodilation and levels of intercellular adhesion molecule-1, C-reactive
protein, homocysteine, and oxidation biomarkers were similar after each
diet. The walnut diet significantly reduced total cholesterol
(-4.4+/-7.4%) and LDL cholesterol (-6.4+/-10.0%) (P<0.05 for both).
Cholesterol reductions correlated with increases of both dietary
alpha-linolenic acid and LDL gamma-tocopherol content, and changes of
endothelium-dependent vasodilation correlated with those of
cholesterol-to-HDL ratios (P<0.05 for all). CONCLUSIONS: Substituting
walnuts for monounsaturated fat in a Mediterranean diet improves
endothelium-dependent vasodilation in hypercholesterolemic subjects. This
finding might explain the cardioprotective effect of nut intake beyond
cholesterol lowering.

Clin Sci (Lond). 2004 Mar;106(3):329-35.
Effects of age and physical fitness on microcirculatory function.
  Sedentary aging is associated with endothelial dysfunction and nitric
oxide (NO) impairment. The aim of the present study was to assess the
effects of regular physical exercise on nitrite/nitrate (NOx)
concentrations and microcirculatory function in older men compared with
young individuals. We measured NOx plasma concentrations and baseline and
stimulated skin blood flow (SBF) by laser Doppler flowmetry in 39 male
athletes [range, 22-72 years; maximal oxygen consumption (VO2max), 60.0
+/- 4.7 ml.min(-1).kg of body weight(-1) (mean +/- S.D.)] and 45 age- and
sex-matched sedentary controls (VO2max, 38.0 +/- 7.1 ml.min(-1).kg of body
weight(-1)). NOx concentrations were higher in athletes than in controls
(50.4 +/- 16.3 compared with 39.0 +/- 15.4 micromol/l; P<0.005), whereas
baseline SBF was comparable. Hand SBF after heating and ischaemia and
foot SBF after heating were higher in athletes (P<0.0001) than in
controls. By comparing the lowest and the highest tertile of age,
sedentary young subjects had higher NOx concentrations than sedentary
older subjects (43.3 +/- 13.4 compared with 31.8 +/- 12.2 micromol/l
respectively; P<0.05). Exercise abolished this difference (49.1 +/-
9.6 micromol/l for young subjects and 52.1 +/- 11.5 micromol/l for older
subjects; not significant). Resting SBF was similar in all the subgroups,
but stimulated SBFs were lower in both subgroups of untrained compared
with trained subjects. NOx concentrations were positively correlated with
VO2max (r=0.46, P<0.001). Stimulated SBFs were correlated with NOx
(r>0.30, P<0.05). These findings show that chronic exercise may improve
endothelial function in older (and young) men, probably by increasing NO

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